Sentinel lymph node (SLN) isolated tumor cells (ITCs) in otherwise stage I/II endometrioid endometrial cancer: To treat or not to treat?

OBJECTIVES: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC). METHODS: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS. RESULTS: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS. CONCLUSIONS: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.

Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study.

OBJECTIVE: To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. METHODS: Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). RESULTS: The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. CONCLUSIONS: The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

Influence of tumor size on outcomes following pelvic exenteration.

OBJECTIVE: Pelvic exenteration (PE) is often the only curative option for locally advanced or recurrent pelvic malignancies. Despite radical surgery, recurrence risk and morbidity remain high. In this study, we sought to determine tumor size effect on perioperative outcomes and subsequent survival in patients undergoing PE. METHODS: Retrospective chart review was performed for female patients who underwent PE at two comprehensive cancer centers from 2000 to 2015. Demographics, complications and outcomes were recorded. Statistical analyses were performed using chi-square, student's t-test, logistic regression, non-parametric tests, log-rank test, and Cox proportional hazards. RESULTS: Of 151 women who underwent PE, 144 had available pathologic tumor size. Gynecologic oncology, surgical oncology, and urology performed 84, 29, and 31 exenterations, respectively. Tumor dimensions ranged from 0 to 25.5cm. Perioperative complications, 30-day mortality, reoperation, and readmission rates were not associated with tumor size. Obesity and prior radiation increased risk for major perioperative complication while anterior exenterations decreased risk. Larger tumors were more likely to undergo total pelvic exenteration (OR 1.14; 95%CI 1.03-1.27), have positive margins (OR 1.11; 95%CI 1.02-1.22), and recur (65%, 42% and 20% for tumors >4cm, ≤4cm and no residual tumor respectively, p=0.016). Tumor size >4cm and positive margins were associated with worse overall survival amongst gynecologic oncology patients. CONCLUSION: Tumor size was not associated with perioperative morbidity. Larger tumors were associated with positive margins, more extensive resection, and worse survival in gynecologic oncology patients. Larger studies are needed to further understand tumor size impact on PE outcomes within specific tumor types.

The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role.

BACKGROUND: Forkhead box protein A2 (FOXA2) plays an important in development, cellular metabolism and tumorigenesis. The Cancer Genome Atlas (TCGA) identified a modest frequency of FOXA2 mutations in endometrioid endometrial cancers (EEC). The current study sought to determine the relationship between FOXA2 mutation and clinicopathologic features in EEC and FOXA2 expression. METHODS: Polymerase chain reaction (PCR) amplification and sequencing were used to identify mutations in 542 EEC. Western blot, quantitative reverse transcriptase PCR (qRT-PCR) and immunohistochemistry (IHC) were used to assess expression. Methylation analysis was performed using combined bisulfite restriction analysis (COBRA) and sequencing. Chi-squared, Fisher's exact, Student's t- and log-rank tests were performed. RESULTS: Fifty-one mutations were identified in 49 tumors (9.4% mutation rate). The majority of mutations were novel, loss of function (LOF) (78.4%) mutations, and most disrupted the DNA-binding domain (58.8%). Six recurrent mutations were identified. Only two tumors had two mutations and there was no evidence for FOXA2 allelic loss. Mutation status was associated with tumor grade and not associated with survival outcomes. Methylation of the FOXA2 promoter region was highly variable. Most tumors expressed FOXA2 at both the mRNA and protein level. In those tumors with mutations, the majority of cases expressed both alleles. CONCLUSION: FOXA2 is frequently mutated in EEC. The pattern of FOXA2 mutations and expression in tumors suggests complex regulation and a haploinsufficient or dominant-negative tumor suppressor function. In vitro studies may shed light on how mutations in FOXA2 affect FOXA2 pioneer and/or transcription factor functions in EEC.

Effect of chemotherapy delays and dose reductions on progression free and overall survival in the treatment of epithelial ovarian cancer.

INTRODUCTION: Hematologic, gastrointestinal, and neurologic complications are common side effects of the platinum and taxane-based chemotherapy used in the primary treatment of epithelial ovarian cancer (EOC). These side effects and the impact of the resultant chemotherapy dose modification on disease free interval have not been extensively studied. The goal of this study was to determine the effect of chemotherapy delays and dose reductions on progression free survival (PFS) and overall survival (OS). METHODS: A review of patients with primary epithelial ovarian, peritoneal, and fallopian tube carcinoma treated between 1/2000 and 12/2007 was performed. Inclusion criteria were advanced stage disease and first line chemotherapy with a platinum and taxane regimen. Cox proportional hazard models were used to determine the effect of chemotherapy reductions and delays on PFS and OS. RESULTS: One hundred and fifty seven patients met the inclusion criteria. Patients were divided into four groups: no delays or reductions (48%), delay only (27%), reduction only (8%), and both delay and reduction (18%). The mean number of delays/reductions per patient was 1.1 (range=0-5) and therapy was delayed a mean of 8 days. The most common reasons for delays/reductions were neutropenia (n=51), thrombocytopenia (n=45), and neuropathy (n=18). There were no differences detected in PFS or OS between groups. CONCLUSIONS: There were no differences detected in survival between patients who required dose adjustments and treatment delays and those who did not. The lack of association between survival and chemotherapy alterations suggests that in specific circumstances patients with advanced ovarian cancer should have individualized treatment plans.

Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab?

BACKGROUND: Increased rates of bowel perforation in patients with recurrent epithelial ovarian cancer (EOC) treated with bevacizumab have been reported, but the risk factors for this association are uncertain. We sought to identify factors associated with bowel perforation and fistula formation in recurrent EOC patients treated with bevacizumab. METHODS: A chart review of all patients treated with bevacizumab for recurrent EOC at a single institution was performed. Pertinent patient characteristics and treatment information were collected. Univariate logistic regression was performed to analyze multiple variables. RESULTS: One hundred twelve patients who were treated with 160 different bevacizumab regimens were identified. The median age was 60 years (range, 29-78 years). Patients had received a median of 4 prior chemotherapy regimens (range, 1-10). The median number of cycles was 4 (range, 0.5-31). Ten patients (9%) were diagnosed with bowel perforations, and another 2 patients (1.8%) were diagnosed with fistulas. The 30-day mortality following perforation was 50%, with 30% of patients dying within 1 week. Patients with rectovaginal nodularity were more likely to develop a bowel perforation or fistula than those who did not have this finding, OR=3.64 (95% CI=1.1 to 12.1, p=0.04). None of the other variables were significantly associated with bowel perforations or fistula formation. CONCLUSIONS: Rectovaginal nodularity is associated with an increased risk of bowel perforation or fistula formation for patients with recurrent EOC treated with bevacizumab. Careful consideration should be given prior to initiating bevacizumab treatment in EOC patients with rectovaginal nodularity since the mortality rate with bevacizumab associated bowel perforations is 50%.

The effect of preoperative nutritional status on postoperative complications and overall survival in patients undergoing pelvic exenteration: A multi-disciplinary, multi-institutional cohort study.

INTRODUCTION: Optimization of preoperative nutritional status has been recommended and associated with improved outcomes for other oncologic procedures, but has not been studied in patients undergoing pelvic exenteration. METHODS: A retrospective chart review of 199 patients was conducted. Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analysis was performed with Cox proportional hazards. RESULTS: 199 patients underwent PE with 61 (31%), 78 (40%) and 58 (29%) patients having colorectal, gynecologic and urologic histological diagnoses, respectively. Median OS following PE was 25 months. Preoperative serum albumin <3.5 g/dL was associated with worsened OS (HR 1.661; 95% CI 1.052-2.624) as well as increased incidence of any postoperative complication (85.9% vs 72.3%, p = 0.034), but was not associated with 90-day mortality (11.3% vs 7.9%, p = 0.457). CONCLUSION: Poor preoperative nutritional status is associated with increased complications and decreased OS. Surgeons should maximize preoperative nutritional status to improve perioperative outcomes and long-term survival.